OZOBAX DS

1 INDICATIONS AND USAGE OZOBAX DS is indicated for the treatment of spasticity resulting from multiple sclerosis, particularly for the relief of flexor spasms and concomitant pain, clonus, and muscular rigidity. OZOBAX DS may also be of some value in patients with spinal cord injuries and other spinal cord diseases. Limitations of Use OZOBAX DS is not indicated in the treatment of skeletal muscle spasm resulting from rheumatic disorders. OZOBAX DS is a gamma-aminobutyric acid (GABA-ergic) agonist indicated for the treatment of spasticity resulting from multiple sclerosis, particularly for the relief of flexor spasms and concomitant pain, clonus, and muscular rigidity. ( 1 ) OZOBAX DS may also be of some value in patients with spinal cord injuries and other spinal cord diseases. ( 1 ) Limitations of Use OZOBAX DS is not indicated in the treatment of skeletal muscle spasm resulting from rheumatic disorders ( 1 )

2 DOSAGE AND ADMINISTRATION Baclofen oral solution is available in multiple concentrations; include both the total dose in mg and the total dose in volume on prescriptions ( 2.1 ) Initiate OZOBAX DS with a low dosage, preferably in divided doses, administered orally. Increase gradually based on clinical response and tolerability. ( 2.2 ) The maximum dosage is 80 mg daily (20 mg four times a day). ( 2.2 ) When discontinuing, reduce the dosage slowly. ( 2.3 ) 2.1 Important Dosage Information Baclofen oral solution is available in multiple concentrations; ensure accuracy when prescribing, dispensing and administering baclofen oral solution to avoid dosing errors due to confusion between mg and mL, and with other baclofen oral solutions of different concentrations. When writing prescriptions, include both the total dose in mg and the total dose in volume. 2.2 Recommended Dosage Initiate OZOBAX DS with a low dosage, preferably in divided doses, administered orally. The following gradually increasing dosage regimen is suggested, but should be adjusted based on clinical response and tolerability: 5 mg (2.5 mL) three times a day for three days 10 mg (5 mL) three times a day for three days 15 mg (7.5 mL) three times a day for three days 20 mg (10 mL) three times a day for three days Additional increases may be necessary up to the maximum recommended dosage of 80 mg daily (20 mg four times a day). 2.3 Discontinuation of OZOBAX DS When discontinuing OZOBAX DS, reduce the dosage slowly and avoid abrupt withdrawn from the drug to help minimize the risk of adverse reactions [see Warnings and Precautions ( 5.1 )].

4 CONTRAINDICATIONS OZOBAX DS is contraindicated in patients with hypersensitivity to baclofen. Hypersensitivity to baclofen ( 4 )

5 WARNINGS AND PRECAUTIONS Abrupt discontinuation of baclofen has resulted in serious adverse reactions including death; therefore, reduce the dosage slowly when OZOBAX DS is discontinued. ( 5.1 ) Neonatal withdrawal symptoms can occur; gradually reduce the dosage and discontinue OZOBAX DS before delivery. ( 5.2 ) OZOBAX DS can cause drowsiness and sedation. Patients should avoid the operation of automobiles or other dangerous machinery until they know how the drug affects them. Advise patients that the central nervous system effects of OZOBAX DS may be additive to those of alcohol and other CNS depressants. ( 5.3 ) OZOBAX DS can cause exacerbation of the following: psychotic disorders, schizophrenia, or confusional states; autonomic dysreflexia; epilepsy. Use with caution in patients with these conditions ( 5.5 , 5.6 , 5.7 ) 5.1 Adverse Reactions from Abrupt Withdrawal of OZOBAX DS Abrupt discontinuation of baclofen, regardless of the cause, has resulted in adverse reactions that include hallucinations, seizures, high fever, altered mental status, exaggerated rebound spasticity, and muscle rigidity, that in rare cases has advanced to rhabdomyolysis, multiple organ-system failure, and death. Therefore, reduce the dosage slowly when OZOBAX DS is discontinued, unless the clinical situation justifies a rapid withdrawal. 5.2 Neonatal Withdrawal Symptoms Withdrawal symptoms in neonates whose mothers were treated with oral baclofen throughout pregnancy have been reported starting hours to days after delivery. The symptoms of withdrawal in these infants have included increased muscle tone, tremor, jitteriness, and seizure. If the potential benefit justifies the potential risk to the fetus and OZOBAX DS is continued during pregnancy, gradually reduce the dosage and discontinue OZOBAX DS before delivery. If slow withdrawal is not feasible, advise the parents or caregivers of the exposed neonate of the potential for neonatal withdrawal. 5.3 Drowsiness and Sedation Drowsiness and sedation have been reported in up to 63% of patients taking baclofen, the active ingredient in OZOBAX DS [see Adverse Reactions ( 6.1 )] . Patients should avoid operation of automobiles or other dangerous machinery and activities made hazardous by decreased alertness when starting OZOBAX DS or increasing the dose until they know how the drug affects them. Advise patients that the central nervous system depressant effects of OZOBAX DS may be additive to those of alcohol and other CNS depressants. 5.4 Poor Tolerability in Stroke Patients OZOBAX DS should be used with caution in patients who have had a stroke. Baclofen has not significantly benefited patients with stroke. These patients have also shown poor tolerability to the drug. 5.5 Exacerbation of Psychotic Disorders, Schizophrenia, or Confusional States OZOBAX DS should be used with caution in patients suffering from psychotic disorders, schizophrenia, or confusional states. If treated with OZOBAX DS, these patients should be kept under careful surveillance because exacerbations of these conditions have been observed with oral baclofen administration. 5.6 Exacerbation of Autonomic Dysreflexia OZOBAX DS should be used with caution in patients with a history of autonomic dysreflexia. The presence of nociceptive stimuli or abrupt withdrawal of OZOBAX DS may cause an autonomic dysreflexic episode. 5.7 Exacerbation of Epilepsy OZOBAX DS should be used with caution in patients with epilepsy. Deterioration in seizure control has been reported in patients taking baclofen. 5.8 Posture and Balance Effects OZOBAX DS should be used with caution in patients where spasticity is utilized to sustain upright posture and balance in locomotion or whenever spasticity is utilized to obtain increased function. 5.9 Ovarian Cysts A dose-related increase in incidence of ovarian cysts was observed in female rats treated chronically with oral baclofen. Ovarian cysts have been found by palpation in about 4% of the multiple sclerosis patients who were treated with oral baclofen for up to one year. In most cases, these cysts disappeared spontaneously while patients continued to receive the drug. Ovarian cysts are estimated to occur spontaneously in approximately 1% to 5% of the normal female population.

7 DRUG INTERACTIONS 7.1 CNS Depressants and Alcohol OZOBAX DS can cause CNS depression, including drowsiness and sedation, which may be additive when used concomitantly with other CNS depressants or alcohol [see Warnings and Precautions ( 5.3 )].

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Adverse Reactions from Abrupt Withdrawal of OZOBAX DS [see Warnings and Precautions ( 5.1 )] Neonatal Withdrawal Symptoms [see Warnings and Precautions ( 5.2 )] Drowsiness and Sedation [see Warnings and Precautions ( 5.3 )] Poor Tolerability in Stroke Patients [see Warnings and Precautions ( 5.4 )] Exacerbation of Psychotic Disorders, Schizophrenia, or Confusional States [see Warnings and Precautions ( 5.5 )] Exacerbation of Autonomic Dysreflexia [see Warnings and Precautions ( 5.6 )] Exacerbation of Epilepsy [see Warnings and Precautions ( 5.7 )] Posture and Balance Effects [see Warnings and Precautions ( 5.8 )] Ovarian Cysts [see Warnings and Precautions ( 5.9 )] The most common (up to 15% or more) adverse reactions in patients were drowsiness, dizziness, and weakness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Metacel Pharmaceuticals, LLC at 1-833-469-6229 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reaction is transient drowsiness. In one controlled study of 175 patients, transient drowsiness was observed in 63% of those receiving baclofen compared to 36% of those in the placebo group. Other common adverse reactions (up to 15%) are dizziness and weakness. Adverse reactions with a frequency of ≥1% are listed in Table 1. Table 1. Common (≥1%) Adverse Reactions in Patients Treated with Baclofen for Spasticity ADVERSE REACTION PERCENT Drowsiness 10-63% Dizziness 5-15% Weakness 5-15% Nausea 4-12% Confusion 1-11% Hypotension 0-9% Headache 4-8% Insomnia 2-7% Constipation 2-6% Urinary Frequency 2-6% Fatigue 2-4% The following adverse reactions not included in Table 1, classified by body system, were also reported: Neuropsychiatric: euphoria, excitement, depression, hallucinations, paresthesia, muscle pain, tinnitus, slurred speech, coordination disorder, tremor, rigidity, dystonia, ataxia, blurred vision, nystagmus, strabismus, miosis, mydriasis, diplopia, dysarthria, epileptic seizure Cardiovascular: dyspnea, palpitation, chest pain, syncope Gastrointestinal: dry mouth, anorexia, taste disorder, abdominal pain, vomiting, diarrhea, and positive test for occult blood in stool Genitourinary: enuresis, urinary retention, dysuria, impotence, inability to ejaculate, nocturia, hematuria Other: rash, pruritus, ankle edema, excessive perspiration, weight gain, nasal congestion The following laboratory tests have been found to be abnormal in patients receiving baclofen: increased SGOT, elevated alkaline phosphatase, and elevation of blood sugar.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ) Because baclofen is excreted unchanged through the kidneys it may be necessary to reduce the dosage in patients with impaired renal function. ( 8.6 ) 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of OZOBAX DS in pregnant women. Oral administration of baclofen to pregnant rats resulted in an increased incidence of fetal structural abnormalities at a dose which was also associated with maternal toxicity. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions Ozobax DS may increase the risk of late-onset neonatal withdrawal symptoms [see Warnings and Precautions ( 5.2 )] . Data Animal Data Baclofen given orally has been shown to increase the incidence of omphaloceles (ventral hernias) in fetuses of rats given approximately 13 times on a mg/kg basis, or 3 times on a mg/m 2 basis, the maximum oral dose recommended for human use; this dose also caused reductions in food intake and weight gain in the dams. This abnormality was not seen in mice or rabbits. 8.2 Lactation Risk Summary At recommended oral doses, baclofen is present in human milk. There are no human data on the effects of baclofen on milk production. There are no adequate data on the effects of baclofen on the breastfed infant. Withdrawal symptoms can occur in breastfed infants when maternal administration of OZOBAX DS is stopped, or when breastfeeding is stopped [see Warnings and Precautions ( 5.2 )] . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for OZOBAX DS and any potential adverse effects on the breastfed infant from OZOBAX DS or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients below the age of 12 have not been established. 8.5 Geriatric Use In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Renal Impairment Because baclofen is primarily excreted unchanged through the kidneys, OZOBAX DS should be given with caution to patients with renal impairment, and it may be necessary to reduce the dosage.